The purpose of the project is to determine the incidence rates, rates of progression, and risk factors for the chronic complications of NIDDM. The study is conducted in the Pima Indians of the Gila River Indian Community, who have participated in a longitudinal epidemiologic study since 1965 (see project Z01 DK 69000). Risk factors for the major complications of diabetes, retinopathy, nephropathy, and coronary artery disease, are determined by longitudinal followup of diabetic subjects. Methods of ascertainment of these complications include fundus photography, measurement of urine albumin and serum creatinine concentrations, and electrocardiography. The degree of urinary albumin excretion (indicating kidney disease in diabetes) is greater in Pima Indians than in several other American Indian tribes, even when controlled for other risk factors such as duration of diabetes, degree of hyperglycemia, and hypertension. This suggests that unidentified genetic or environmental risk factors for nephropathy are more common in the Pimas. Genetic loci potentially affecting susceptibility to two complications of diabetes have been identified. Among diabetic Pima Indians, the 4G allele of the promoter of the plasminogen activator inhibitor-1 gene is associated with a doubling of the risk of diabetic retinopathy. A study of siblings affected with diabetic nephropathy suggests that a still unknown gene near the marker D7S1804 is linked to nephropathy. The HLA genes also appear to have a role in vascular disease, as Pima Indians of HLA type A2 have a 5-fold elevated cardiovascular disease mortality rate compared with other Pimas. Although the degree of hyperglycemia predicts occurrence of complications, the opposite is also true, at least in the case of periodontitis. Severe periodontitis predicted worsening glycemic control, indicating that control of oral infections may be important, and often overlooked, aspect of diabetes management.